Sex Specificity in Methadone Analgesia in the Rat: A Population Pharmacokinetic and Pharmacodynamic Approach

Purpose. To quantify the extent to which a sex-specific dichotomy in the temporal evolution of the analgesic effect, after intravenous (i.v.) methadone injection in the rat, relates to the pharmacokinetics (PK) and pharmacodynamics (PD) that mediate the dose-to-effect pathway.Methods. Tail-flick analgesia was measured after i.v. methadone injection (0.35 mg/kg) in female (n = 16) and male (n = 16) Sprague-Dawley rats. The PK were evaluated in separate female (n = 56) and male (n = 56) rats after they had received the same dose of methadone i.v. (0.35 mg/kg). A bicompartmental model described the kinetics and a sigmoid E_max model-related drug effect vs. simulated concentrations (pharmacodynamics) at the times of effect measurement. All model parameters as well as interanimal and assay variabilities were estimated with a mixed-effects population method using the program NONMEM.Results. The area under the effect-time curve (AUCE_0-120) was (mean ± interanimal SD) 1859 ± 346 min in the females, which was significantly lower than the 4871 ± 393 min in the males (P < 0.0001). On the contrary, the profiles of concentration vs. time were higher in females and, therefore, corresponded inversely to the effect vs. time-relative magnitudes. The central volume of distribution, V1, was 1.94 ± 0.37 l/kg for female rats and 3.01 ± 0.33 l/kg for male rats. Also, the central clearance was 0.077 ± 0.006 l/min/kg and 0.102 ± 0.005 l/min/kg, respectively, for female and male rats. Both parameters differed significantly between sexes (P < 0.0001). The pharmacodynamic maximum observed effect parameter (E_max) was 37% ± 29% in female rats and 85% ± 16% in male rats, and these values were significantly different (P < 0.0001). The parameter for the concentration eliciting half of E_max (EC₅₀) was 24.1 ± 7.5 g/l in female rats and 20.3 ± 2.9 g/l in male rats, and the Hill-related exponent, , was 6.3 ± 3.9 in female rats and 5.5 ± 4.1 in male rats. These parameters did not differ significantly (at the P < 0.05 level).Conclusions. A sex-specific dichotomy in the methadone antinociceptive effect, in the rat, was not proportionally related to plasma concentrations. Each sex corresponded to a distinct subpopulation of the PK parameters and one of the pharmacodynamic parameters (E_max). When the course of a drug involves PK or PD subpopulations, PK/PD modeling can afford the safest prediction of the effect-time evolution for a particular dose.